1. Field of the Invention
This invention relates to a polymeric composition having antimicrobial properties and a process for rendering the surface of a substrate antimicrobial. The polymeric composition is a crosslinked chemical combination of (i) a polymer having amino group-containing side chains along a backbone forming the polymer, (ii) an antimicrobial agent selected from metals, metal alloys, metal salts, and metal complexes, and (iii) a crosslinking agent containing functional groups capable of reacting with the amino groups on the polymer.
2. Description of the Related Art
Many medical procedures involve the placement of medical devices, such as catheters, endotracheal tubes, prostheses, grafts, sutures, dressings and implants, in the human body. Infection is a common complication associated with the use of such medical devices. Accordingly, many research efforts have concentrated on finding means to prevent infection associated with these medical devices.
One solution to this infection problem has been the use of medical device coatings having metallic antimicrobial agents. An xe2x80x9cantimicrobialxe2x80x9d agent is an agent that has antiviral, antibacterial, and/or antifungal properties. (Antiviral means capable of killing, or suppressing the replication of, viruses. Anti-bacterial means bacteriostatic or bactericidal. Bactericidal means the killing of microorganisms. Bacteriostatic means inhibiting the growth of microorganisms. Antifungal means capable of killing or suppressing replication of fungi.) It has been particularly desirable to use a coating for implantable medical devices that is bacteriostatic, i.e., inhibits bacterial growth, such that the device can be implanted for longer periods without compromising the subject through a secondary bacterial infection. For example, U.S. Pat. No. 4,054,139 discloses a catheter coated with a silver-based material that reduces infection; U.S. Pat. No. 4,603,152 discloses a medical device coated with an antimicrobial composition including a polymeric binder and an antimicrobial metal compound such as a silver salt; U.S. Pat. No. 4,933,178 discloses a medical device having an antimicrobial coating comprising a polymeric material and a metal (e.g., silver, gold, zinc, platinum, copper) salt of sulfonylurea; and U.S. Pat. No. 5,019,096 discloses an infection resistant material used on medical devices which includes a polymeric component (e.g., polyurethane or silicone) and a silver salt.
Even though various medical device coatings having metallic antimicrobial agents are known, there is still a need for an improved antimicrobial polymer coating that may be easily applied to a substrate to provide an article which has excellent antimicrobial properties and which retains its antimicrobial properties in a permanent and non-leachable fashion when in contact with bodily fluids for prolonged periods. In addition, it would be beneficial if this coating could be combined with an anti-thrombogenic coating to prevent both clotting and bacterial infection. There is also a need for antimicrobial coatings that are useful in fields other than medical devices, such as antifouling applications for aqueous and marine environments, and corrosion control.
The foregoing needs are met by a polymeric composition having antimicrobial properties, wherein the polymeric composition comprises a crosslinked chemical combination of (i) a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group, (ii) an antimicrobial agent selected from metals, metal alloys, metal salts, metal complexes and mixtures thereof, and (iii) a crosslinking agent containing at least two functional groups capable of reacting with the amino groups. An article according to the invention comprises a substrate and a coating of the polymeric composition disposed on at least a portion of the substrate.
The polymer used in the polymeric composition comprises a polymer having side chains along a backbone forming the polymer wherein at least two of the side chains contain an amino group ( xe2x80x94NRH, xe2x80x94NH2, xe2x80x94NRH2+, xe2x80x94NH3+). In one example embodiment, the polymer is a polyamide having amino substituted alkyl chains on one side of the polymer backbone. The crosslinking agent used in the polymeric composition contains at least two functional groups capable of reacting with the amino groups of the polymer used in the coating. In one example of the crosslinking agent used in the polymeric composition, the crosslinking agent is selected from the group consisting of phosphines having the general formula (A)3P, wherein A is hydroxyalkyl, and mixtures thereof. One more specific example of the crosslinking agent used in the polymeric composition is tris(hydroxymethyl)phosphine. Specific non-limiting examples of the metallic antimicrobial agent used in the polymeric composition include chelated silver ions, silver metal, chelated copper ions, copper metal, chelated zinc ions, zinc metal and mixtures thereof.
An article having an antimicrobial surface may be produced by a process according to the invention in which a polymer having at least two amino substituted side chains is mixed with a metallic antimicrobial agent and a crosslinking agent to produce a polymer solution. The crosslinking agent contains at least two crosslinking functional groups which react and combine with amino groups on the polymer. The polymer solution is coated on at least a portion of a substrate to produce a crosslinked antimicrobial polymer coating on the substrate.
In an example embodiment of the invention, the versatile chemical methodology of the invention allows for the deposition of an antimicrobial polymeric composition on a polymeric substrate (e.g., polydimethylsiloxane, polyurethane, and polypropylene). The polymeric composition includes a two dimensional polymer having a backbone of repeating xcex2-amino acid units with long aliphatic side-chain and free NHxe2x80x94 and NH2xe2x80x94substituents and may be synthesized by condensation of 2(5H)-furanone, or maleic acid derivatives (such as anhydride, esters, and so on) with a long-chain amine (e.g., tetradecylamine) and a polyamine (e.g., pentaethylenehexamine). Crosslinking of the two-dimensional polymer is undertaken with tris(hydroxymethyl)phosphine (the crosslinking agent) and a metallic antimicrobial agent such as chelated silver ions, silver metal, chelated copper ions, copper metal, chelated zinc ions, and zinc metal.
Experimental studies indicate that when chelated silver ions, silver metal, chelated copper ions, copper metal, chelated zinc ions or zinc metal are incorporated into the two-dimensional polymer and the polymer is crosslinked with the crosslinking agent, the resulting polymeric composition exhibits strong inhibitory activity against target pathogenic microorganisms. When the polymeric composition comprises: (a) first crosslinked chemical combination of (i) the polymer, (ii) a first antimicrobial agent selected from metals, metal alloys, metal salts, and metal complexes, and (iii) the crosslinking agent; and (b) a second crosslinked chemical combination of (i) the polymer, (ii) a second different antimicrobial agent selected from metals, metal alloys, metal salts, and metal complexes, and (iii) the crosslinking agent, a galvanic cell is formed between the two different metals or ions that provides synergistic antimicrobial activity greater than the sum of the activity of the individual metals or ions alone.
It is therefore an advantage of the present invention to provide an improved antimicrobial polymeric composition that may be easily applied to a substrate to produce an article which has excellent antimicrobial properties and which retains its antimicrobial properties in a permanent and non-leachable fashion when placed in an environment (e.g., bodily fluids) that may promote bacterial growth.
It is another advantage of the present invention to provide an improved antimicrobial polymeric composition that may be easily applied to a substrate for the prevention of medical device-related infections.
It is a further advantage of the present invention to provide an improved antimicrobial polymeric composition that may be easily applied to a substrate along with an anti-thrombogenic coating to prevent both clotting and bacterial infections.
It is yet another advantage of the present invention to provide an improved antimicrobial polymeric composition that may be easily applied to a substrate for antifouling applications for aqueous and marine environments.
It is still another advantage of the present invention to provide an improved antimicrobial polymeric composition that may be easily applied to a substrate for corrosion control coatings.
These and other features, aspects, and advantages of the present invention will become better understood upon consideration of the following detailed description, drawings, and appended claims.